Leishmania are representative of hemoflagellate protozoa and are intracellular parasites of mammalian tissues. The organisms are highly successful in their ability to grow and multiply in tissues of the reticuloendothelial system. It is remarkable that these are the very tissues of the vertebrate host which are ordinarily responsible for hostile reactions to invading foreign organisms. In the reticuloendothelial system, the parasites lie within the host macrophage for at least part of their life cycle. Fusion of host cell secondary lysosomes with the parasitophorous vacuoles apparently occurs without preventing subsequent multiplication of the Leishmania. Such fusion may provide means for access for nutrients to the parasite, but also exposes the parasite to host antibodies and lysosomal enzymes. Despite the potentially hostile intracellular environment, the organisms survive and multiply within the host macrophages. The consequences of leishmanial invasion of the reticuloendothelial system are highly dependent upon a complex interplay of parasite strains and cellular immune responses of the vertebrate host. In man, the result of successful invasion of the spleen and liver most frequently is death. Such infections with Leishmania donovani, and other leishmanial strains, are transmitted by the bite of an infected sandfly. Scarring of the skin may be the sole manifestation of infection with Leishmania tropica and allied dermatotropic organisms (as, Leishmania aethiopica, L. mexicana, L. peruviana, and L. guyanensis). Intermediate in severity are invasions of muco-cutaneous tissues by Leishmania braziliensis. There are considerable differences among various animals in their response to leishmanial infections; however, a satisfactory animal model for laboratory trials has been found in Leishmania donovani infections in the golden hamster.
Relatively few drugs have been found effective against leishmanial disease in man. Antimony drugs are a mainstay for treatment despite evaluation of diverse types both in the laboratory and in clinical trials. Pentavalent compounds of antimony are better tolerated than trivalent antimonials, yet severe toxic side effects may occur, in particular among poorly nourished patients. Toxicity of such drugs may affect the liver (hepatitis), kidneys (nephritis), or the heart (myocarditis). Of these toxic effects, myocarditis is the greatest and most common problem.
Liposomes are defined as closed vesicles, or sacs, which contain phospholipids (examples of which are lecithin and sphingomyelin) and which may contain other lipids (examples of which are cholesterol and other sterols or steroids; charged lipids such as dicetyl phosphate and octadecylamine; glycolipids; and also lipid-soluble vitamins). When shaken in the presence of water, with the water being at least 50% (w/w) compared to phospholipid, the lipid mixture is formed into discrete particles consisting of concentric spherical shells of lipid bilayer membranes which are separated by aqueous interspaces; these are referred to as multilamellar liposomes (MLL). Upon sonication, the MLL are converted to small unilamellar liposomes (ULL). In 1965, it was demonstrated that the MLL vesicle membranes were completely closed and did not allow escape of a marker compound present in the aqueous interspaces; similar properties later were found for ULL.
Numerous studies have shown that liposomes, upon injection into animals and man, are taken up rapidly by cells, and intra-cellular lysosomes, of the reticuloendothelial system, particularly those in the liver. Because of the relative impermeability of liposomes, and speedy removal of them from the circulatory system, substances in the aqueous interspaces of liposomes remain concentrated and are unexposed to plasma. These characteristics of liposomes suggested that they might have a potential for application as carriers for anti-leishmanial agents, particularly antimonial drugs. The cells and tissues in which the liposomes are readily taken up are the very locations in which the Leishmania organisms predominantly reside, thus raising the possibility that liposomes might carry concentrated doses of antimonial agents directly to organisms residing within reticuloendothelial cells of the spleen and liver. Not only would the drugs be directed more effectively to tissues and cells harboring the obligate intra-cellular Leishmania, but also the encapsulated drugs would have decreased liability for producing toxic side-effects through exposure to blood. Moreover, there would be strong probability for prolonged effectiveness of the drug through slow biodegradation of the multilamellar membrane structure of the liposomes. The characteristics of liposomes suggest their suitability as carrier for other antiparasitic agents.